In order to treat or prevent hematologic disorders of leukocytes, it is essential to understand the process of maturation of functional cells from bone marrow precursors. I propose to study the process of myeloid differentiation with the objective of better understanding the development of human granulocyte function and the basis of disorders of phagocytosis. The chemically-induced differentiation of the human promyelocytic leukemia cell line HL-60 provides a model system for the study of the biochemical correlates of functional maturation. These studies will include a) changes in the composition and synthesis of membrane and contractile proteins; b) the formation and functional role of secondary granules; and c) the contents and activities in the respiratory burst of membrane cytochrome b, NADPH oxidase, and glutathione peroxidase. Lone-term cultures of human bone marrow produce granulocytes that will be examined for a) in vitro reproduction of the defects in growth or function in hematologic diseases of phagocytes, such as agranulocytosis, chemotactic disorders, and Chediak-Higashi syndrome; and b) the relative contributions of hematopoietic stem cells and bone marrow stroma to the pathogenesis of these disorders. Manipulations of both systems will examine the functional consequences of a) perturbations of cyclic nucleotide levels; b) the addition of antimetabolites and other cytotoxic drugs; and c) inhibition of transmethylation reactions.